T32 Proposal ?Cancer Targets and New Drug Discovery? ABSTRACT The goal of the T32 training program ?Cancer Targets and New Drug Discovery? is to establish an innovative multi-thematic graduate student and postdoctoral training program (?the Program?) to train the next generation of leaders in cancer target discovery and validation, cancer drug discovery, and biomarker development. This goal will be attained by a 2 year training program for 1 graduate student and 3 postdoctoral trainees, who will be trained in the skills needed to execute a successful cancer drug discovery program using novel paradigms and state-of-the-art technologies. The program uniquely includes a 2-month biotech company internship and training in scientific entrepreneurship specifically focused on new cancer target and drug discovery, as well as research entrepreneurship. The Specific Aims of the Program are: 1) To discover and validate novel cancer drug targets. Training will focus on critically validating new targets in the context of signaling networks, mechanisms of genetic and epi-genetic regulation, and also on exploring non-traditional targets, for example, targeting components of tumor stroma, which is important for supporting cancer cell growth and providing a barrier to attack by immune cells. The genetic stability of the stroma may also render the putative targets less susceptible to developing resistance; 2) To discover small molecule probes to interrogate novel cancer targets. SBP has the technically most advanced and largest chemical library screening program of any academic organization. Our strong expertise in structurally-based rational drug design using NMR and X-ray crystallography will provide training opportunities in probe discovery using both approaches; 3) To conduct mechanistic studies of cancer signaling pathways using probe inhibitors. We will provide training in the use of small molecule probes in cells and preclinical animal models to provide insights into the practical application of drugs to treat cancer, signaling interactions, mechanisms of resistance and potential biomarkers; and 4) To provide entrepreneurial training. Given that fewer than 15% of trainees can expect to have a faculty appointment in academia, we will provide the trainees experience in biopharma research as a possible alternate career. We are located in the second largest hub of biotech companies in the United States, and working with a corporate biotech incubator partner, will provide a unique entrepreneurial T32 training experience with a 2-month cancer biotech internship.